High dose ranolazine formulations

ABSTRACT

Mycophenolate mofetil, mycophenolic acid, and ranolazine can be conveniently manufactured into high dose oral formulations by the hot melt filling of a supercooled mycophenolate mofetil, mycophenolic acid, or ranolazine liquid into a pharmaceutical dosage form. High dose oral pharmaceutical formulations and manufacturing methods therefor are disclosed.

This is a continuation-in-part of application Ser. No. 08/061,656, filedMay 13, 1993.

FIELD OF THE INVENTION

The present invention relates to mycophenolate mofetil, mycophenolicacid, and ranolazine, particularly to improved formulations thereof, andspecifically to high dose formulations. The invention is also directedto methods of manufacturing the formulations.

BACKGROUND INFORMATION

Mycophenolic acid ("MPA") , chemically known as6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid was initially described as a weakly-activeantibiotic found in the fermentation broth of Penicilliumbrevicompactum, having the following structure. ##STR1## MPA and certainrelated compounds, such as mycophenolate mofetil (the morpholinoethylester of MPA, chemically known as morpholinoethylE-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate),having the following structure: ##STR2## have more recently beendescribed as having particularly advantageous therapeutic properties,e.g., as immunosuppressant drugs. See, for example, U.S. Pat. Nos.3,880,995; 4,727,069; 4,753,935; and 4,786,637, all incorporated hereinby reference.

MPA and mycophenolate mofetil, notwithstanding the improved oralbioavailability characteristics of the latter, require daily doses onthe order of 2.0 to as much as 3.5 or 4.0 grams per day (or even 5.0grams per day in the case of MPA, for example as described in U.S. Pat.No. 3,880,995) depending upon the patient and the disease state beingtreated. Using a conventional dosage formulation containing 250 mg in astandard size 1 (0.48 cc volume) capsule, a patient receiving a 3.0 gramdaily dose is required to take twelve capsules each day, giving rise topatient convenience and compliance concerns. It has remained desired toprovide high dose oral formulations for MPA and mycophenolate mofetil,particularly in view of their relatively high daily doses.

Ranolazine, known chemically(±)N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, is described in U.S. Pat. No. 4,567,264 as havingadvantageous therapeutic properties, e.g., for cardiovascular diseaseincluding arrhythmias, variant and exercise induced angina andmyocardial infarction and for treatment of tissues experiencing aphysical or chemical insult, including treating cardioplegia, hypoxicand/or reperfusion injury to cardiac or skeletal muscle or brain tissue,and for use in transplants.

The filling of molten or thixotropic liquids and pastes into hardgelatin capsules has been described as a way of reducing the problems ofconventional pharmaceutical processing methods, and adaptations ofcapsule filling machines for this purpose have been described in theliterature See, e g., Walker, et al., "The filling of molten andthixotropic formulations into hard gelatin capsules,"J.Pharm.Pharmacol., Vol. 32, 389-393 (1980); and McTaggart, et al., "Theevaluation of an automatic system for filling liquids into hard gelatincapsules," J. Pharm. Pharmacol., Vol. 36, 119-121 (1984). The advantagesof this formulation technology have been described as including "lowcontent uniformity variation, reduced dust generation giving rise toreduced cross contamination hazards, controlled dissolution rate usingsolid solution or slow release systems, the ability to process lowmelting point or liquid drugs and the possibility of in-houseformulation development and manufacture" (McTaggart, et al., at page119). Liquid-filled hard-gelatin capsule formulations have beenparticularly suggested for "drugs that have low melting points, drugsthat are low-dosed or that are oxygen- or moisture-labile, and drugsthat require bioavailability enhancement" including "the development ofsustained-release formulations." Cole, "Liquid Filled Hard GelatinCapsules," Pharm. Technol., Vol. 13, No. 9, 134-140 at 134 (1989).

More recently, a new aspect of liquid-paste filling was reported"whereby a high fill weight of a low-melting thermostable drug(ibuprofen) can be attained using low levels of excipient whilstpreserving the facility to obtain a wide range of drug release rates."Smith, et al., "The filling of molten ibuprofen into hard gelatincapsules," Int. J. Pharm., Vol. 59, 115-119 at 115 (1990). There,ibuprofen (m.p. 77° C.) was heated to 70°-80° C., alone and with avariety of excipients, and filled into a variety of capsule sizes.Maximum approximate fill weights for ibuprofen alone, of 450 mg (size1), 605 mg (size 0), 680 mg (size 0 elongated), and 825 mg (size 00),were reported.

Mycophenolate mofetil has a melting point of 95° C. MPA has a meltingpoint of 141° C. Ranolazine free base has a melting point of 120° C.None is a low-melting drug that would be considered suitable for hotmelt filling, particularly given an upper fill temperature of 80° C.,preferably below 60° C., for hard gelatin capsules due to their ownmelting characteristics. It was surprisingly discovered thatmycophenolate mofetil, once heated above its melting point, has theunexpected property of remaining liquid for sustained periods of timeafter cooling to significantly lower temperatures. Such a considerabledelay in solidification even after cooling below melting point (a"supercooling" phenomena) was reported as "a problem" to be overcome inthe preparation of medications in the form of pearls (see U.S. Pat. No.5,188,838).

In the present invention, mycophenolate mofetil's ability to besupercooled has been extended by the application of that discovery tohot melt filling, to produce previously unattainable high doseformulations. It has also been discovered that MPA exhibits the abilityto be supercooled, and while the duration is shorter than that measuredfor mycophenolate mofetil, MPA's supercooling duration is sufficient forproducing previously unattainable high dose formulations.

SUMMARY OF THE INVENTION

It has surprisingly been discovered that mycophenolate mofetil, MPA, andranolazine can be conveniently manufactured into high dose oralformulations by the hot melt filling of a supercooled mycophenolatemofetil, MPA, or ranolazine liquid into a pharmaceutical dosage form.

One aspect of the invention relates to a pharmaceutical formulationhaving a therapeutically effective amount of mycophenolate mofetil, themycophenolate mofetil having been liquefied by heating to a firsttemperature above about 95° C., then cooled to a second temperaturebelow about 80° C. at which the mycophenolate mofetil remainedliquefied, followed by filling the mycophenolate mofetil into apharmaceutical dosage form while in said cooled liquefied state. In apreferred embodiment, the formulation includes a disintegrant such ascroscarmellose sodium.

In another aspect, the invention relates to high dose formulations ofmycophenolate mofetil, having 500 mg in a size 1 capsule, 750 mg in asize 0 capsule, or 1000 mg in a size 00 capsule.

Still another aspect of the invention relates to methods formanufacturing a pharmaceutical formulation of MPA or mycophenolatemofetil, including the steps of:

liquefying the active agent by heating it to a first temperature aboveits melting point;

cooling the liquefied active agent to a second temperature below itsmelting point, at which second temperature the active agent remainsliquefied; and

filling the liquefied active agent into a pharmaceutical dosage form.

In a preferred aspect, the manufacturing method includes the steps of:

liquefying mycophenolate mofetil by heating it to a temperature aboveabout 95° C. (preferably to about 95°-120° C.);

admixing croscarmellose sodium, in an amount sufficient to serve as adispersant in the formulation when finished, with the liquefiedmycophenolate mofetil;

cooling the admixed liquefied mycophenolate mofetil and croscarmellosesodium to a temperature below about 80° C. (preferably below about 60°C.); and

filling the cooled, liquefied mycophenolate mofetil admixed withcroscarmellose sodium into hard or soft capsules.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and General Parameters

The following definitions are set forth to illustrate and define themeaning and scope of the various terms used to describe the inventionherein.

Reference to the active agent employed in the formulations of thepresent invention, "mycophenolate mofetil," is intended to include thepharmaceutically acceptable salts thereof, and, "ranolazine", isintended to include the pharmaceutically acceptable salts thereof.

The size and volume of the capsules employed in the formulations of thepresent invention include the following:

    ______________________________________                                               SIZE  VOLUME                                                           ______________________________________                                                1    0.48 cc                                                                  0    0.67 cc                                                                 0 EL  0.74 cc                                                                 00    0.95 cc                                                          ______________________________________                                    

as described in the Shinogi (formerly Elanco) Qualicaps capsuleTechnical Information Manual (F6,200, p. 10).

Materials

Mycophenolate mofetil can be made as described in U.S. Pat. No.4,753,935, previously incorporated by reference. Mycophenolic acid iscommercially available, e.g., from Sigma Chemical Company, St. Louis,Mo. Ranolazine can be made as described in U.S. Pat. No. 4,567,264,incorporated herein by reference. Pharmaceutically acceptableexcipients, hard and soft gelatin capsules, cellulosic capsules (alsoreferred to as starch based capsules, commercially available from WarnerLambert) and capsule filling machinery are commonly commerciallyavailable.

Formulations

Mycophenolate mofetil, MPA, or ranolazine can be employed as the activeagent in the formulations of the present invention, either alone or incombination with pharmaceutically acceptable excipients and/or othermedical agents. Generally, the formulation will contain about 90% to100%, preferably about 95% to 96% by weight of active agent, theremainder being suitable pharmaceutical excipients, carriers, etc,preferably about 4% by weight of a disintegrant (most preferablycroscarmellose sodium).

Normally employed excipients include, for example, disintegrants (suchas croscarmellose sodium, sodium carboxymethylcellulose, crosspovidone,sodium starch glycolate or the like), diluents (such as lactose,sucrose, dicalcium phosphate, or the like), lubricants (such asmagnesium stearate or the like), binders (such as starch, gum acacia,gelatin, polyvinylpyrrolidine, cellulose and derivatives thereof, andthe like), viscosity aids (such as cellulose) and crystal modifying aids(such as sodium chloride). A crystal retardant or poison [such assorbitol 5-7% w/w (e.g., as described by Thomas, et al., "The Use ofXylitol as a Carrier for Liquid-Filled Hard-Gelatin Capsules," Pharm.Tech Int., Vol. 3, 36, 38-40 (1991) incorporated herein by reference)hydroxypropylmethyl cellulose, or hydroxypropylcellulose]can be added toan active agent that exhibits supercooling (stays liquid below itsmelting temperature) for a time period less than that optimally desiredfor dosage form filling, for example prior to or after the active agenthas been liquefied.

The mycophenolate mofetil formulations of the invention have atherapeutically effective amount of mycophenolate mofetil, themycophenolate mofetil having been liquefied by heating to a firsttemperature above about 95° C., then cooled to a second temperaturebelow about 80° C. at which the mycophenolate mofetil remainedliquefied, followed by filling the mycophenolate mofetil into apharmaceutical dosage form, such as a capsule (e.g., a hard gelatincapsule, a soft gelatin capsule, or a cellulosic capsule) or a tabletmold (e.g., by injection molding) while in said cooled liquefied state.Tablets formulations of the invention are preferably coated with apharmaceutically acceptable coating material (such as opadry,commercially available from Coloron, Inc. of West Point, Pa.) forexample by spray coating or other coating methods conventionallyemployed in the field.

In a preferred embodiment, particularly for capsules, the formulationsinclude croscarmellose sodium, admixed with liquefied mycophenolatemofetil prior to cooling in an amount sufficient to serve as adisintegrant.

Preferred formulations include mycophenolate mofetil (95-100% w/w, mostpreferably 96% w/w) and croscarmellose sodium (0-5% w/w, most preferably4% w/w), filled into a gelatin capsule.

Manufacturing Methods

The methods for manufacturing a pharmaceutical formulations of includethe steps of:

liquefying the active agent by heating it to a first temperature aboveits melting point;

cooling the liquefied active agent to a second temperature below itsmelting point, the active agent remaining liquefied at the secondtemperature; and

filling the liquefied active agent into a pharmaceutical dosage form.

Once filled, the liquefied active agent is allowed to solidify.

A preferred manufacturing method, where the active agent ismycophenolate mofetil, includes the steps of:

liquefying mycophenolate mofetil by heating it to a temperature aboveabout 95° C. (preferably about 95° to 120° C.);

admixing croscarmellose sodium (in an amount sufficient to serve as adisintegrant in the formulation when finished) with the liquefiedmycophenolate mofetil;

cooling the admixed liquefied mycophenolate mofetil and croscarmellosesodium to a temperature below about 80° C. (preferably below about 60°C., most preferably about 35° to 45° C.); and

filling the cooled, liquefied mycophenolate mofetil admixed withcroscarmellose sodium into hard or soft capsules (preferably usingtemperature controlled filling apparatus adjusted to the temperature ofthe cooled admixture).

The cooling and mixing rates can be optimized depending upon theparticular active agent, manufacturing process, size and equipmentemployed. While the underlying theory for formulating supercooledliquids is not completely understood (for example, it remainsunpredictable whether a given active agent will exhibit supercooling atall, as illustrated below in Example 6), particularly for larger scalemanufacturing processes, some factors to be considered include stirringrate (e.g., for mycophenolate mofetil it can be advantageous to avoidcausing sheer forces when stirring, or to eliminate stirringaltogether), stirring equipment (e.g., overhead or magnetic bar),cooling rate, cooling temperature, and filling equipment temperature.

Formulations prepared by the above-described process of the inventionmay be identified by the solid (as opposed to compacted powder orgranule) contents of a capsule. For example, mycophenolate mofetil formsa friable, solid, off-white mass when cooled in a capsule. The presenceof such a solid mass is a method of detecting a formulation made by theinvention and/or use of a process of the invention.

Preferred Processes

In a presently preferred process, mycophenolate mofetil is liquefied byheating it to a temperature above about 95° C.; croscarmellose sodium isadmixed with the liquefied mycophenolate mofetil in an amount sufficientto serve as a disintegrant in the formulation when finished; the admixedliquefied mycophenolate mofetil and croscarmellose sodium are cooled toa temperature below about 80° C. (most preferably below about 60° C.);and the cooled, liquefied mycophenolate mofetil admixed withcroscarmellose sodium is filled into hard or soft capsules.

Preferred Formulations

Presently preferred is the formulation of 96% w/w mycophenolate mofetiland 4% w/w croscarmellose sodium, most preferably in a size 1 hardgelatin capsule containing 500 mg active ingredient, in a size 0 hardgelatin capsule containing 750 mg active ingredient, or in a size 00hard gelatin capsule containing 1000 mg active ingredient.

Administration

The formulations of the present invention are useful for oraladministration in any oral treatment regimen for MPA, mycophenolatemofetil, or ranolazine. While human dosage levels have yet to befinalized, generally, a daily dose of mycophenolate mofetil ormycophenolic acid is from about 2.0 to 5.0 grams, preferably about 2.0to 3.5 grams. The amount of active compound administered will, ofcourse, be dependent on the subject and disease state being treated, theseverity of the affliction, the manner and schedule of administrationand the judgment of the prescribing physician. For example, a treatmentregimen for administering 3.0 grams of mycophenolate mofetil per day,which previously entailed taking 6 size 1 capsules (250 mg) twice daily,when administered with a formulation of the present invention entailstaking 2 size 0 capsules (750 mg) twice daily.

EXAMPLES

The following examples are given to enable those skilled in the art tomore clearly understand and to practice the present invention. Theyshould not be considered as limiting the scope of the invention, butmerely as being illustrative and representative thereof.

Example 1

Mycophenolate mofetil (50 g) was added to a 250 ml beaker and melted ona hot plate at low setting. The molten material was allowed to cool to40°-50° C. at which temperature it remained a liquid, which was drawninto a 20 ml disposable syringe using the plunger. The syringe was usedto fill the body of a size 0 hard gelatin capsule using the luerconnection as a fill nozzle. The material was dispensed bottom up,withdrawing the nozzle as fill proceeded. The capsule cap was thenplaced on the filled body and the closed capsule allowed to standovernight, to give a high dose mycophenolate mofetil capsule.

The above-described procedure can be used to produce batches of 20 to 30size 0 high dose capsules of mycophenolate mofetil.

Example 2

This example illustrates the preparation of a 2.0 kg batch of arepresentative high dose pharmaceutical formulation for oraladministration containing mycophenolate mofetil as the active compound.

Mycophenolate mofetil (1920 g; 96% w/w) is added to a jacketed kettle.The temperature is raised to a temperature between 95° and 120° C.Croscarmellose sodium (80 g; 4% w/w) is added to the jacketed kettlewith mixing. The temperature is lowered to a temperature between 35° and45° C., with continued mixing. The cooled mixture (750 mg) is filledinto the bodies of 2,500 size 0 hard gelatin capsules (allowing for asmall amount of surplus), the temperature of the filling apparatus beingadjusted to between 35° and 45° C.

Example 3 Alternative Dosage Forms

Soft Capsules

By following the procedure of Example 1 or 2, and substituting softgelatin capsules for the hard gelatin capsules there-employed and usingthe rotary die filling process, there are obtained the correspondingsoft-gelatin capsule dosage forms.

Cellulosic Capsules

By following the procedure of Example 1 or 2, and substitutingcellulosic capsules for the hard gelatin capsules there-employed andcooling the molten material to 80° C., there are obtained thecorresponding cellulosic capsule dosage forms.

Example 4

Mycophenolic acid 90% w/w (90 g) is added to a 500 ml beaker and meltedon a hot plate at a temperature of 145° C. To the molten material isadded croscarmellose sodium 4% w/w (4 g) and sorbitol 6% w/w (a 70%solution, added dropwise) with gentle mixing. The mixture is allowed tocool to 50°-60° C., at which temperature it remains a liquid, which isdrawn into a 20 ml disposable syringe using the plunger. The syringe isused to fill the body of a size 0 hard gelatin capsule using the luerconnection as a fill nozzle. The capsule cap is then placed on thefilled body and the closed capsule allowed to stand overnight, to give ahigh dose mycophenolic acid capsule.

Example 5 Determination of Average and Maximum Fill Weight For DifferentCapsule Sizes

Mycophenolate mofetil hard gelatin capsule formulations weremanufactured according to the procedures described in Example 1 andfilled into hard gelatin capsules of various sizes. The average (n=6)and maximum fill weights for each size were calculated, and are reportedbelow.

    ______________________________________                                        SIZE    VOLUME       AV. FILL  MAX. FILL                                      ______________________________________                                         1      0.48 cc      508 mg    580 mg                                          0      0.67 cc      767 mg    810 mg                                         0 EL    0.74 cc      n/a       890 mg                                         00      0.95 cc      1037 mg   1080 mg                                        ______________________________________                                    

The formulations of the present invention contained significantly moremycophenolate mofetil per capsule (1058 mg/cc) than did conventionalformulations such as 250 mg of mycophenolate mofetil in a size 1 capsule(520 mg/cc).

Example 6 Supercooling Test

Mineral oil (15 ml) in a 50 ml beaker is heated to a predeterminedtemperature in excess of the melting point of the compound to be tested,using a hotplate. A 2-5 g sample of test compound (a solid at roomtemperature) is weighed into a scintillation vial, and the vial isplaced into the preheated mineral oil. The test compound is allowed tomelt, after which the scintillation vial is removed from the mineral oiland allowed to return to room temperature. Changes in the appearance ofthe test compound, including recrystallization, and the time beforesolidification are recorded.

When mycophenolate mofetil (m.p. 95° C.) was employed as the testcompound in the above procedure, and heated to 120° C., the compoundremained a liquid at room temperature for up to two hours. Mycophenolatemofetil, heated to melting and filled into size 0 capsules,recrystallized in the capsule to form a solid mass when stored at roomtemperature conditions for approximately 12 hours.

Mycophenolic acid (m.p. 141° C.), when tested in the above procedure andheated to melting, after cooling to room temperature did not exhibitcrystal seed nucleation for about ten minutes, and remained a liquid for35 minutes prior to complete recrystallization. Mycophenolic acid plusone drop of a 70% solution of sorbitol (about 7% wt/wt) when tested inthe above procedure and heated to melting, after cooling to roomtemperature did not exhibit crystal seed nucleation for about tenminutes, and remained a liquid for over 1 hour.

Similarly, when tested in the above procedure and heated to 120° C.(melting):

trenbelone acetate (m.p. 97° C.), methocarbamol (m.p. 94° C.), captopril(m.p. 87°/104° C.), and ranolazine (m.p. 120° C.) remained a liquid atroom temperature for at least two hours;

gemfibrozil (m.p. 58° C.), guaifenesin (m.p. 79° C.), flurbiprofen (m.p.110° C.), and flutamide (m.p. 112° C.) remained a liquid for about 10minutes; and

nabumetone (m.p. 80) recrystallized immediately.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A pharmaceutical formulation comprising atherapeutically effective amount of ranolazine, said ranolazine havingbeen heated to a first temperature above its melting point, cooled to asecond temperature below its melting point at which second temperaturesaid ranolazine remained liquefied, and filled into a pharmaceuticaldosage form while in said cooled liquefied state.
 2. The pharmaceuticalformulation of claim 1 wherein said pharmaceutical dosage form is acapsule.
 3. The pharmaceutical formulation of claim 2 wherein saidsecond temperature is lower than the melting point of said capsule. 4.The pharmaceutical formulation of claim 1 further comprising a secondmaterial in admixture with said ranolazine, said admixed ranolazine andsecond material having been heated to a temperature above the meltingpoint of the mixture, said second material being a second active agentor a pharmaceutically acceptable excipient.
 5. The pharmaceuticalformulation of claim 1 further comprising a pharmaceutically acceptabledisintegrant.
 6. The pharmaceutical formulation of claim 5 wherein saiddisintegrant is croscarmellose sodium.
 7. The pharmaceutical formulationof claim 1 further comprising a crystal retardant.
 8. The pharmaceuticalformulation of claim 7 wherein said crystal retardant is sorbitol.
 9. Amethod for manufacturing a pharmaceutical formulation of ranolazine,comprising the steps of:liquefying the ranolazine by heating it to afirst temperature above its melting point; cooling said liquefiedranolazine to a second temperature below its melting point, at whichsecond temperature said ranolazine remains liquefied; and filling saidcooled liquefied ranolazine into a pharmaceutical dosage form.
 10. Themethod of claim 9 wherein said pharmaceutical dosage form is a capsule.11. The method of claim 10 wherein said second temperature is lower thanthe melting point of said capsule.
 12. The method of claim 9 furthercomprising the step of admixing a second material with said ranolazine,said second material being a second active agent or a pharmaceuticallyacceptable excipient; wherein said liquefying step comprises heatingsaid admixed ranolazine and second material to a temperature above themelting point of the mixture.